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Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-04-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00264
Elvira Bruno 1 , Maria Rosa Buemi 1 , Anna Di Fiore 2 , Laura De Luca 1 , Stefania Ferro 1 , Andrea Angeli 3 , Roberto Cirilli 4 , Daniele Sadutto 4 , Vincenzo Alterio 2 , Simona Maria Monti 2 , Claudiu T. Supuran 3 , Giuseppina De Simone 2 , Rosaria Gitto 1
Affiliation  

On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (2333) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (Ki = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.

中文翻译:

探索人类碳酸酐酶(hCAs)与一类新型苯甲磺酰胺之间的分子相互作用

根据hCA II与4-(3,4-二氢-1 H-异喹啉-2-羰基)苯磺酰胺(3)(PDB代码4Z1J)的配合物的X射线晶体学研究,4-设计了(1-芳基-3,4-二氢-1 H-异喹啉-2-羰基)苯磺酰胺(2333)。具体而言,我们的想法是通过引入其他疏水/亲水功能来提高对可药物异构体的选择性。在合成和测试的化合物中,(RS)-4-(6,7-二羟基-1-苯基-3,4-四氢异喹啉-1 H -2-羰基)苯磺酰胺(30)对大脑表达的hCA VII(K i = 0.20 nM )表现出显着的抑制作用,并且对更广泛分布的hCA I和hCA II同工型具有选择性。通过对映选择性HPLC,我们解析了外消旋混合物,并确定了两种对映异构体(30a30b)是hCA VII的等活性抑制剂。晶体学和对接研究揭示了这些抑制剂与碳酸酐酶(CA)催化位点之间的主要相互作用,从而突显了非极性接触对于此类hCA抑制剂的相关作用。
更新日期:2017-05-10
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